Various compounds of 4,5-diarylpyrrole derivatives are known (see, for example, Japanese Unexamined Patent Publication No. 54-79271 (1979); U.S. Pat. No. 4,652,582; Japanese Patent Publication No. 48-38704 (1973)).
Nonsteroidal anti-inflammatory agents serve to inhibit cyclooxygenase (COX) in its mechanism of action. Cyclooxygenase is known to have two subtypes, i.e., cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and conventional nonsteroidal anti-inflammatory agents inhibit both the subtypes. COX-1 is constantly present in gastrointestinal tract and so on and causes adverse side effects such as gastrointestinal disorders when inhibited. On the other hand, COX-2 appears only when an inflammation occurs and, therefore, a compound which selectively inhibits COX-2 is expected as a drug with minimal side effects [Mebio, Vol. 11, No. 10, p. 80 (1994)]. Further, it has been reported that COX-2 is involved in proliferation of colon cancer and, therefore, the COX-2 selective inhibitor is also expected as an antitumor agent (CANCER RESEARCH, Vol. 55, 3785 (1995)).
The compounds of the above-mentioned conventional techniques exhibit strong anti-inflammatory action; however, there has been a problem of adverse side effects such as gastrointestinal tract disorders since the compounds do not have selectivity with respect to the cyclooxygenase or, even if the selectivity is known, the inhibitory activity is insufficient.
Among 4,5-diarylpyrrole derivatives, examples of the compounds whose COX-2 inhibitory activity is described are found in J. Med. Chem., Vol. 38, 3895 (1995), Med. Chem. Res., Vol. 5, No. 5, 399 (1995), J. Med. Chem., Vol. 37, 988 (1994). In the literatures, the enhanced anti-inflammatory action is realized mainly by introducing electron withdrawing groups on 2- and 3-positions of 4,5-diarylpyrrole; however, the selective inhibitory activity of COX-2 is rather suppressed in the compounds to which the electron withdrawing groups are introduced as substituents than, for example, that of the compounds wherein the 2- and 3-positions of 4,5-diarylpyrrole are hydrogen atoms. Further, the literatures do not disclose any examples of electron donating groups as the substituents for the 2- and 3-positions. Moreover, no description of the cytostatic action is given in the literatures.
The object of the present invention is to provide an anti-inflammatory agent and antitumor agent which selectively inhibit COX-2 without adverse side effects such as gastric disorder.
The present invention relates to compounds represented by General Formula (1): ##STR2##
wherein,
R.sup.1 represents a hydrogen atom or lower alkyl group. PA1 R.sup.2 represents a lower alkyl group or (CH.sub.2).sub.n1 COOH and n1 is 1, 2 or 3. PA1 R.sup.3 represents a hydrogen atom, halogen atom, lower alkyl group, hydroxymethyl group, carboxyl group (COOH), lower alkoxycarbonyl group, lower alkoxymethyl group, carbamoyl group (CONH.sub.2), mono-lower alkylcarbamoyl group or di-lower alkylcarbamoyl group. PA1 R.sup.4 represents a phenyl group, bicyclic heteroaryl group or phenyl ethynyl group which may optionally be substituted by a functional group selected from the group consisting of a lower alkyl group, halogen atom, lower alkoxy group, lower alkylthio group, nitro group, alkanoyl group, cyano group, amino group, mono-lower alkylamino group, di-lower alkylamino group, alkanoylamino group and alkanoyloxy group; or lower alkynyl group. PA1 R.sup.5 represents a lower alkyl group, amino group, mono-lower alkylamino group or di-lower alkylamino group, and a salt thereof; and an anti-inflammatory agent and antitumor agent which comprise said compounds as the active ingredients. PA1 R.sup.1 represents a hydrogen atom or lower alkyl group. PA1 R.sup.2 represents a lower alkyl group or (CH.sub.2).sub.n1 COOH and n1 is 1, 2 or 3. PA1 R.sup.3 represents a hydrogen atom, halogen atom, lower alkyl group, hydroxymethyl group, carboxyl group (COOH), lower alkoxycarbonyl group, lower alkoxymethyl group, carbamoyl group (CONH.sub.2), mono-lower alkylcarbamoyl group or di-lower alkylcarbamoyl group. PA1 R.sup.4 represents a phenyl group, bicyclic heteroaryl group or phenylethynyl group which may optionally be substituted by a functional group or groups selected from the group consisting of a lower alkyl group, halogen atom, lower alkoxy group, lower alkylthio group, nitro group, alkanoyl group, cyano group, amino group, mono-lower alkylamino group, di-lower alkylamino group, alkanoylamino group and alkanoyloxy group; or lower alkynyl group, PA1 R.sup.5 represents a lower alkyl group, PA1 R.sup.6 represents a hydrogen atom or lower alkyl group, and Z represents a halogen atom. PA1 R.sup.4 and R.sup.5 are as defined above. Z represents a halogen atom. PA1 R.sup.1 to R.sup.5 are as defined above. Z represents a halogen atom. PA1 R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as described above. W represents B(OH).sub.2 or Sn(n-Bn).sub.3. PA1 R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.6 are as defined above. R.sup.7 and R.sup.8 are the same or different and represent a hydrogen atom or lower alkyl group, and W represents B(OH).sub.2 or Sn(n-Bu).sub.3. PA1 R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above. W represents B(OH).sub.2 or Sn(n-Bu).sub.3.
Examples of the lower alkyl group include C.sub.1 -C.sub.6 alkyl groups having linear or branched chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl and hexyl group.
Examples of the halogen atom include a chlorine atom, bromine atom, fluorine atom and iodine atom. Examples of the lower alkoxycarbonyl group include C.sub.1 -C.sub.6 alkoxycarbonyl groups having linear or branched chain, such as a methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl and t-butoxycarbonyl. Examples of the lower alkoxy group include C.sub.1 -C.sub.6 alkoxy groups having linear or branched chain such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.
Examples of the lower alkoxymethyl group include C.sub.2 -C.sub.5 lower alkoxymethyl groups, such as methoxymethyl, ethoxymethyl, isopropoxymethyl and t-butoxymethyl.
Examples of the mono-lower alkylcarbamoyl group include C.sub.2 -C.sub.5 alkylcarbamoyl groups, such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, i-propylcarbamoyl and n-butylcarbamoyl.
Examples of the di-lower alkyl carbamoyl group include C.sub.3 -C.sub.9 dialkylcarbamoyl groups, such as dimethylcarbamoyl, diethylcarbamoyl, di(n-propyl)carbamoyl and di(n-butyl)carbamoyl.
Examples of the lower alkylthio group include C.sub.1 -C.sub.6 alkylthio groups having linear or branched chain, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthlo, isobutylthio, sec-butylthio, t-butylthio, pentylthio and hexylthio.
Examples of the lower alkanoyl group include C.sub.1 -C.sub.4 alkanoyl groups, such as formyl, acetyl, propionyl and butyryl.
Examples of the mono-lower alkylamino group include C.sub.1 -C.sub.6 monoalkylamino groups having linear or branched chain, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, t-butylamino, pentylamino and hexylamino.
Examples of the di-lower alkylamino group include amino groups which are di-substituted by C.sub.1 -C.sub.4 alkyl groups having linear or branched chain, such as dimethylamino, diethylamino, di-n-propylamino, disopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino and di-t-butylamino.
Examples of the alkanoylamino group include C.sub.1 -C.sub.4 alkanoylamino groups, such as formylamino, acetylamino, propionylamino and butyrylamino.
Examples of the alkanoyloxy groups include C.sub.2 -C.sub.4 alkanoyloxy groups, such as acetyloxy, propionyloxy and butyryloxy.
Where the phenyl group represented by R.sup.4 is mono- substituted by any one of said functional groups, the substitution position may be 2-, 3- or 4-position, preferably 3- or 4-position, and more preferably 4-position. In the case of di-substitution, the substitution positions may be 2- and 3-positions, 2- and 4-positions, 2- and 5-positions, 3- and 5-positions or 3- and 4-positions, preferably 2- and 4-positions or 3- and 4-positions. In the case of tri-substitution, the substitution positions may preferably be 2-, 3- and 4-positions or 3-, 4- and 5-positions. Examples of preferable substituents include a lower alkyl, lower alkoxy, halogen atom, amino, mono- or di-lower alkylamino and lower alkylthio group.
Examples of the bicyclic heteroaryl group which may optionally be substituted by any one of said functional groups preferably include 6-indolyl, 6-N-methylindolyl, 5-indolyl, 5-N-methylindolyl, 5-(2,3-dihydrobenzofuranyl), 6-(2,3-dihydrobenzofuranyl), 4-(3,4-methylenedioxyphenyl) and 3-(3,4-methylenedioxyphenyl). The bicylic heteroaryl group is a group whose one ring is a benzene ring and the other ring is a 5-membered or 6-membered ring containing 1 or 2 hetero atoms, N, O or S. Examples of substituents for the bicyclic heteroaryl group include the functional groups, i.e., a lower alkyl group, halogen atom, lower alkoxy group, lower alkylthio group, nitro group, alkanoyl group, cyano group, amino group, mono-lower alkylamino group, di-lower alkylamino group, alkanoylamino group, and alkanoyloxy group, preferably a lower alkyl, halogen atom, hydroxyl group, lower alkoxy, amino, mono- or di-lower alkylamino, lower alkylthio and, in particular, a methyl group.
Examples of substituents for the phenylethynyl group include said functional groups, i.e., a lower alkyl group, halogen atom, lower alkoxy group, lower alkylthio group, nitro group, alkanoyl group, cyano group, amino group, mono-lower alkylamino group, di-lower alkylamino group, alkanoylamino group, and alkanoyloxy group, preferably a lower alkyl, halogen atom, lower alkoxy, amino, mono- or di-lower alkylamino, lower alkylthio and, in particular, a methyl group.
Examples of the alkynyl groups include C.sub.2 -C.sub.6 alkynyl groups, such as ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group.
Examples of substituents for the phenylethynyl group include said functional groups, preferably a lower alkyl, lower alkoxy, halogen atom, amino, mono- or di-lower alkylamino, and lower alkylthio.
R.sup.1 preferably represents a hydrogen atom, methyl or ethyl, more preferably a hydrogen atom or methyl, particularly preferably a hydrogen atom.
Preferable R.sup.2 may be a lower alkyl group, in particular, a methyl group.
Preferable R.sup.3 may be a hydrogen atom.
Preferable R.sup.4 may be a phenyl which is mono-substituted or di-substituted by any one of said functional groups, 6-indolyl, 6-N-methylindolyl, 5-indolyl, 5-N-methylindolyl, 5-(2,3-dihydrobenzofuranyl), 6-(2,3-dihydrobenzofuranyl), 4-(3,4-methylenedioxyphenyl), 3-(3,4-methylenedioxyphenyl), phenylethynyl, ethynyl and propynyl.
Particularly preferably, R.sup.4 may be a lower alkyl, lower alkoxy, halogen atom, amino group, mono- or di-lower alkylamino, phenyl group which is mono-substituted or di-substituted by a lower alkylthio, 6-N-methylindolyl, 5-N-methylindolyl, 5-(2,3-dihydrobenzofuranyl), 6-(2,3-dihydrobenzofuranyl) or phenylethynyl group.
Preferable R.sup.5 may be methyl, NH.sub.2 or NHMe, more preferably methyl or NH.sub.2, and particularly preferably methyl.
Compounds of the General Formula (1) of the present invention can be prepared, for example, in accordance with the following &lt;Reaction Scheme 1&gt;. ##STR3##
wherein,